title: Ceramide promotes apoptosis in chronic myelogenous leukemia-derived K562 cells by a mechanism involving caspase-8 and JNK.
abstract: Ceramide is a sphingolipid that activates stress kinases such as p38 and c-JUN N-Terminal Kinase (JNK). Though Chronic Myelogenous Leukemia (CML) derived K562 cells resist killing by short chain C2-ceramide, we report here that longer chain C6-ceramide promotes apoptosis in these cells. C6-ceramide induces cleavage of Caspase-8 and Caspase-9, but only Caspase-8 is required for apoptosis. The sphingolipid killed CML derived KBM5 cells and, to a lesser extent, imatinib-resistant KBM5-STI cells suggesting that BCR-ABL can not completely block C6-ceramide-induced apoptosis but the kinase may regulate the process. BCR-ABL is known to suppress Protein Phosphatase 2A (PP2A) in CML cells. While C6-ceramide can activate PP2A in acute leukemia cells, the sphingolipid did not activate the phosphatase in K562 cells. C6-ceramide did not activate p38 kinase but did promote JNK activation and phosphorylation of JUN. Inhibition of JNK by pharmacological agent protected K562 cells from C6-ceramide suggesting that JNK plays an essential role in C6-ceramide mediated apoptosis. Furthermore, the sphingolipid promoted MCL-1 phosphorylation by a mechanism that, at least in part, involves JNK. The findings presented here suggest that Caspase-8, JNK, and perhaps MCL-1 may play important roles in regulating cell death and may represent new targets for therapeutic strategies for CML.
authors.affiliation: Institute of Molecular Medicine, University of Texas Health Science Center, Houston, Texas, USA.
authors.forename: Alina Felicia
authors.initials: AF
authors.lastname: Nica
authors.forename: Chun Chui
authors.initials: CC
authors.lastname: Tsao
authors.forename: Julie C
authors.initials: JC
authors.lastname: Watt
authors.forename: Tilahun
authors.initials: T
authors.lastname: Jiffar
authors.forename: Svitlana
authors.initials: S
authors.lastname: Kurinna
authors.forename: Paul
authors.initials: P
authors.lastname: Jurasz
authors.forename: Marina
authors.initials: M
authors.lastname: Konopleva
authors.forename: Michael
authors.initials: M
authors.lastname: Andreeff
authors.forename: Marek W
authors.initials: MW
authors.lastname: Radomski
authors.forename: Peter P
authors.initials: PP
authors.lastname: Ruvolo
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001549:Benzamides; D053181:Caspase 8 / Q000378:metabolism*; D002518:Ceramides / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000201:enzymology* / Q000473:pathology*; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D054648:Protein Phosphatase 2 / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D001549:Benzamides; D002518:Ceramides; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D054648:Protein Phosphatase 2; D053181:Caspase 8